Improving long-term renal allograft survival remains an elusive goal. Chronic immune-mediated injury in the form of antibody against donor HLA (donor specific alloantibody, DSA) is increasingly recognized as one of the major causes of late renal allograft loss and there is no effective treatment. Renal transplantation in sensitized patients (i.e. those with DSA at baseline) provides a powerful model to study the pathobiology of chronic antibody-mediated injury. Sensitized patients are increasing in numbers and they have very few options for transplantation other than a positive crossmatch kidney transplant. Our group has performed more than 250 positive crossmatch kidney transplants. One year allograft survival rates are now >90%, however, serial protocol biopsies suggest that by 5 years after transplant >80% of these patients develop chronic injury manifested as transplant glomerulopathy (TG). Allografts with TG have very poor long- term survival with >50% failing within 5 years of diagnosis. While the patients studied will be those with DSA at the time of transplant, we believe that these results will be applicable to a wider group of kidney transplant recipients (and other organ transplant recipients) who develop de novo DSA after transplantation. Our central hypothesis is that DSA is the major causative agent in TG. In our Preliminary Data, we show that the proteasome inhibitor, bortezomib, depletes alloantibody-secreting plasma cells resulting in lower serum DSA levels. In Aim 1, we propose a prospective, randomized trial of proteasome inhibition in patients with DSA prior to the development of TG in order to decrease the incidence of TG. In Aim 2, we extend our Preliminary Data by demonstrating that there are distinct histologic and molecular "phenotypes" associated with the outcomes of renal allografts in recipients with DSA. In this aim, we will demonstrate evidence of endothelial cell activation and damage is present at the molecular and ultrastructural level prior to the development of TG by light microscopy. In addition, we will determine if a true accommodation phenotype exists in grafts that do not develop TG by 5 years. One of the central goals of this aim is to identify early markers that precede the development of TG that might be used to direct early intervention aimed at preventing TG. We are uniquely suited to perform these studies given our large volume of patients at risk for TG, our protocolized follow-up (most of the specimens are already collected) and our clinical and laboratory-based expertise in this area. At the end of these studies, we will have a more complete picture of the natural history of TG, a much clearer insight into its causes and will have tested a promising new agent aimed at preventing its development. PUBLIC HEALTH RELEVANCE: Some people who receive a kidney transplant have antibodies against the tissue types of the kidney. These antibodies are made by the recipient's immune system and can destroy the transplant over several years and are one of the major causes of late graft loss. This study aims to understand how these antibodies destroy the kidney and also will test if a new drug can prevent this destruction by blocking the immune system's ability to make these antibodies.